title: Factor Xa activation of factor V is of paramount importance in initiating the coagulation system: lessons from a tick salivary protein.
abstract: BACKGROUND
  Generation of active procoagulant cofactor factor Va (FVa) and its subsequent association with the enzyme activated factor X (FXa) to form the prothrombinase complex is a pivotal initial event in blood coagulation and has been the subject of investigative effort, speculation, and controversy. The current paradigm assumes that FV activation is initiated by limited proteolysis by traces of (meizo) thrombin.
  
  
  RESULTS
  Recombinant tick salivary protein TIX-5 was produced and anticoagulant properties were studied with the use of plasma, whole blood, and purified systems. Here, we report that TIX-5 specifically inhibits FXa-mediated FV activation involving the B domain of FV and show that FXa activation of FV is pivotal for plasma and blood clotting. Accordingly, tick feeding is impaired on TIX-5 immune rabbits, displaying the in vivo importance of TIX-5.
  
  
  CONCLUSIONS
  Our data elucidate a unique molecular mechanism by which ticks inhibit the host's coagulation system. From our data, we propose a revised blood coagulation scheme in which direct FXa-mediated FV activation occurs in the initiation phase during which thrombin-mediated FV activation is restrained by fibrinogen and inhibitors.
authors.affiliation: Center for Experimental and Molecular Medicine, University of Amsterdam, Meibergdreef 9, Room L01-145, 1105 AZ, Amsterdam, The Netherlands. T.J.Schuijt@outlook.com
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Schuijt
authors.forename: Kamran
authors.initials: K
authors.lastname: Bakhtiari
authors.forename: Sirlei
authors.initials: S
authors.lastname: Daffre
authors.forename: Kathleen
authors.initials: K
authors.lastname: Deponte
authors.forename: Simone J H
authors.initials: SJ
authors.lastname: Wielders
authors.forename: J Arnoud
authors.initials: JA
authors.lastname: Marquart
authors.forename: Joppe W
authors.initials: JW
authors.lastname: Hovius
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.forename: Erol
authors.initials: E
authors.lastname: Fikrig
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Bunce
authors.forename: Rodney M
authors.initials: RM
authors.lastname: Camire
authors.forename: Gerry A F
authors.initials: GA
authors.lastname: Nicolaes
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D060829:Arthropod Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D005165:Factor V / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015951:Factor Xa / Q000378:metabolism*; D065427:Factor Xa Inhibitors; D005247:Feeding Behavior; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D018884:Ixodes / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D012471:Salivary Proteins and Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D020349:Surface Plasmon Resonance; D013917:Thrombin / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D060829:Arthropod Proteins; D065427:Factor Xa Inhibitors; D011994:Recombinant Proteins; D012471:Salivary Proteins and Peptides; C583622:TIX-5 protein, tick; D005165:Factor V; D005340:Fibrinogen; D013917:Thrombin; D015951:Factor Xa
keywords: anticoagulants; blood coagulation; ticks